Early activation defects in T lymphocytes from aged mice.
Aging affects both calcium signals and protein kinase cascades in mouse T lymphocytes. The decline in calcium signal development largely represents differences between naive and memory T cells; the latter are resistant to increases in calcium concentration, and are more common in aged mice. Aging leads to declines in phosphorylation of a wide range of substrates in T cells stimulated by either anti-CD3 antibodies or by substances, such as phorbol myristate acetate (PMA) or ionomycin, that act at intracellular sites, but some phosphoproteins respond only in old T cells, and others respond regardless of age. Tyrosine phosphorylation of the CD3 zeta chain declines with age, both in resting T cells and after activation, but the proportion of Zap-70 that is bound to CD3 zeta increases in T cells from old mice. Zap-70 function and phosphorylation of CD3 zeta-associated Zap-70 change only slightly after stimulation of T cells by anti-CD3 and anti-CD4, and are at similar levels in activated old and young T cells. Nonetheless, induction of Raf-1, MEK, and ERK kinase activity declines with age in CD4 T cells. The effect of aging on T-cell activation is not simply an overall decline in signal intensity, but a set of qualitative changes that differ among subsets and depend at least partly on the nature of the stimulus.
Miller
R A
RA
Department of Pathology, University of Michigan, Ann Arbor, USA. millerr@umich.edu
Garcia
G
G
Kirk
C J
CJ
Witkowski
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000375:Aging / Q000276:immunology*; D000818:Animals; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000276:immunology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D017252:CD3 Complex; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D002118:Calcium